(S)-2-(Diphenylacetyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline carboxylic acid, which is one enantiomer of the racemate known as PD 126055, is an angiotensin II type 2 (AT2) receptor antagonist and is described in U.S. Pat. No. 5,246,943 and in Klutchko et al., 1994, Bioorg. & Med. Chem. Lett., 4:57-62.
AT2 receptor antagonists have recently been identified as useful in treating pain, particularly inflammatory pain (WO 2007/106938) and neuropathic pain (WO 2006/066361) and (S)-2-(diphenylacetyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline carboxylic acid:
has been identified as a drug candidate.
Compound 1 has been obtained from the racemate by recrystallization of the α-methylbenzylamine salt (U.S. Pat. No. 5,246,943). However, this method does not provide adequate quantities of Compound 1 with required high levels of chemical and enantiomeric purity necessary for pharmaceutical purposes.
Although the racemate, ie: (R,S)-2-(diphenylacetyl)-1,2,3,4-tetrahydro-6-methoxy-5-phenylmethoxy)-3-isoquinoline carboxylic acid, is a crystalline compound and two different crystalline forms have been identified by the inventors, Compound 1 is an amorphous compound and despite significant effort, no crystalline form of the compound has been identified. There are significant difficulties in developing Compound 1 for pharmaceutical purposes including:                1. the amorphous form is difficult to purify to levels required for pharmaceutical purposes without resorting to expensive and time consuming chromatography methods;        2. the amorphous form of Compound 1 retains residual solvents which are difficult to remove to acceptable levels for pharmaceutical use; and        3. the amorphous form of Compound 1 has very low aqueous solubility and this limits its oral bioavailability.        
There is a need for a form of Compound 1 that is suitable for pharmaceutical development, including a form that can be obtained in large quantities with acceptable chemical purity and enantiomeric purity and that has acceptable aqueous solubility.
The present invention is predicated, at least in part, by the discovery that the sodium salt of Compound 1 had a propensity to form highly crystalline solvates that not only allow this material to be manufactured with improved chemical purity but also allows the enantiomeric purity to be improved by recrystallization in the event that some epimerization occurs at the chiral 3-position of the tetrahydroisoquinoline ring during the manufacturing process. The sodium salt was also found to have good oral bioavailability characteristics.